Unexpected Functions For Alternatively Spliced Proteins

The discovery that a well-studied protein exists in 250 alternatively spliced variants prompts a re-think of protein complexity.

AsianScientist (Jul 30, 2014) – Once assumed to function only in protein translation, aminoacyl tRNA synthetases (AARS) have now been found to exist in myriad forms and perform diverse functions. These findings, which challenge and expand the evolutionary role of alternative splicing, have been published in the journal Science.

“AARS are highly conserved enzymes which are key for turning RNA into proteins. Their role in the process of translation makes them absolutely essential to life and they are found in every living organism on the planet,” said Professor Paul Schimmel, corresponding author of the report, the Ernest and Jean Hahn Professor of Molecular Biology and Chemistry at the Scripps Research Institute (California and Florida) and also a visiting professor of the Hong Kong University of Science and Technology Jockey Club Institute for Advanced Study (IAS).

“Because of the important job that these proteins do, one would anticipate that the structure and sequence of these proteins would be highly conserved and protected from evolutionary pressure. To our surprise, over the course of evolution, these proteins have successfully incorporated new domains that have little to do with canonical enzymatic function.”

Firstly, in order to identify the AARS splice variants, the researchers established a systematic pipeline, developing an AARS transcriptome enrichment method and using high throughput deep sequencing. This led them to discover a staggering 250 previously unknown gene-transcript variants.

“We were amazed to find that this protein family has a large number of splice variants and even more surprised to discover that the specific part of the protein which is devoted to the canonical enzymatic function is largely absent from the spliced forms. This made us very excited to study the splice forms for novel functions,” Prof. Schimmel told Asian Scientist Magazine.

“Therefore, we then studied the AARS variants in the context of expression and distribution across various human tissues, at different developmental stages. We also expressed the variants and examined potential biological activity of novel splice forms in a diverse set of in-vitro cell-based assays.”

One variant selected for analysis turned out to be a powerful driver for the proliferation of muscle fiber cells in a laboratory dish, while others were found to be involved in diverse processes ranging from stem cell biology to immunology.

However, the fact that AARS exist in so many forms does not mean that the variants are examples of alternative splicing gone wrong.

“It is unlikely that the new domains are ‘there by chance’. We hypothesize that these specific domains have been selected for to maintain organismal health and that the production of the resulting novel protein forms is highly regulated and that this plays a critical role in the health of the organism,” Prof. Schimmel said.

“Maintaining homeostasis in an organism is critical for a successful life. Harnessing the power of a ubiquitous protein such as the tRNA synthetase and utilizing it in a spliced form for a new purpose is an evolutionarily sound way for an organism to react to environmental pressure and maintain homeostasis. Thus, we think these new AARS variants may be useful as therapeutics. We have selected a few of these catalytic nulls for deeper investigations of the new biology that has been revealed.”

This work was conducted in collaboration with aTyr Pharma, a company founded by Prof. Schimmel, and the Hong Kong biotech company Pangu Biopharma, an aTyr subsidiary. aTyr Pharma is currently developing several of the AARS variants into therapeutics they call ‘Physiocrines’.

The article can be found at: Lo et al. (2014) Human tRNA Synthetase Catalytic Nulls With Diverse Functions.

———-

Copyright: Asian Scientist Magazine; Photo: Hong Kong University of Science and Technology.
Disclaimer: This article does not necessarily reflect the views of AsianScientist or its staff.

Rebecca did her PhD at the National University of Singapore where she studied how macrophages integrate multiple signals from the toll-like receptor system. She was formerly the editor-in-chief of Asian Scientist Magazine.

Related Stories from Asian Scientist